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bioRxiv · 10.1101/130831

The Calcineurin-FoxO-MuRF1 Signaling Pathway Regulates Myofibril Integrity in Cardiomyocytes

Chen, J.-N.·Shimizu, H.·Langenbacher, A. D.·Huang, J.·Wang, K.·Otto, G.·Geisler, R.·Wang, Y.
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Abstract

Altered Ca2+ handling is often present in diseased hearts undergoing structural remodeling and functional deterioration. The influences of Ca2+ signaling on cardiac function have been examined extensively, but whether Ca2+ directly regulates sarcomere structure has remained elusive. Using a mutant zebrafish model lacking NCX1 activity in the heart, we explored the impacts of impaired Ca2+ homeostasis on myofibril integrity. Gene expression profiling analysis revealed that the E3 ubiquitin ligase MuRF1 is upregulated in ncx1-deficient hearts. Intriguingly, knocking down MuRF1 activity or inhibiting proteasome activity preserved myofibril integrity in ncx1 deficient hearts, revealing a MuRF1-mediated proteasome degradation mechanism that is activated in response to abnormal Ca2+ homeostasis. Furthermore, we detected an accumulation of the MuRF1 regulator FoxO in the nuclei of ncx1-deficient cardiomyocytes. Overexpression of FoxO in wild type cardiomyocytes induced MuRF1 expression and caused myofibril disarray, whereas inhibiting Calcineurin activity attenuated FoxO-mediated MuRF1 expression and protected sarcomeres from degradation in ncx1-deficient hearts. Together, our findings reveal a novel mechanism by which Ca2+ overload disrupts the myofibril integrity in heart muscle cells by activating a Calcineurin-FoxO-MuRF1-proteosome signaling pathway.

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Chen, J.-N., Shimizu, H., Langenbacher, A. D., Huang, J., Wang, K., Otto, G., Geisler, R., Wang, Y.. 2017-04-25. The Calcineurin-FoxO-MuRF1 Signaling Pathway Regulates Myofibril Integrity in Cardiomyocytes. https://doi.org/10.1101/130831

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